It has been established that muscle is the major source of glutamine for the kidney in acute acidosis and attempts will be made to determine whether this is the case for chronic acidosis. The rate of production of glutamine by muscle is likely to be controlled by the balance of activities of the two enzymes, glutamine synthetase and glutaminase. Thus, the levels and the properties of these two enzymes isolated from red and white muscle will be investigated in order to identify possible allosteric regulators. An hypothesis for the control of muscle glutamine biosynthesis will be formulated on the basis of these properties and tested by measurement of the concentrations of metabolic intermediates and allosteric regulators in isolated muscle preparations and in freeze-clamped muscle of the intact animal under conditions in which the rate of glutamine production is modified. There is considerable evidence that alpha-ketoglutarate metabolism in the kidney is a key regulatory step in the glutamine utilization pathway. Consequently, a detailed study of the catalytic properties and allosteric regulation of the enzyme alpha-ketoglutarate dehydrogenase will be carried out. An hypothesis of control will be formulated from the results of this study. This hypothesis will be tested by measuring the concentrations of intermediates of the pathway and identified allosteric regulators in the freeze-clamped, intact kidney and in isolated incubated mitochondria from rats in which the rate of renal glutamine utilization has been changed. The possibility that acid-base disturbances have an effect on the catalytic properties of alpha-ketoglutarate dehydrogenase will also be tested. The inhibitory effect of ketone bodies on glutamine utilization by the kidney will be studied by measuring the effects of these compounds on the flux of glutamine through the ammonia-genic pathways in isolated renal mitochondria. This will enable an hypothesis for the metabolic mechanism of inhibition to be proposed. Further studies in mitochondria from ketotic diabetic animals should demonstrate why the inhibitory effect of ketone bodies is not apparent in this condition. The hypothesis for inhibition will be tested by measuring the effects of ketone bodies on the concentrations of intermediates of the glutamine utilization pathway in perfused kidneys isolated from normal and ketoacidotic rats.